This Is MS Multiple Sclerosis Community: Knowledge & Support

Welcome to the world's leading forum on Multiple Sclerosis research, support, and knowledge. For over 10 years, This is MS has provided an unbiased community dedicated to Multiple Sclerosis patients, caregivers, and affected loved ones.

Advertisement

Efficacy of Tysabri is proven and unsurpassed in well-done FDA quality studies. Therefore, no more efficacy studies need to be done (for Relapsing MS). For marketing purposes, their STARS (Ty versus Reb) study will be interesting, but it will have little scientific value. I suspect they will one day do a secondary progressive MS study and that will have important clinical value and also extend the patent by 6 to 12 months (if it leads to a new indication).

Novantrone got approved with 2 small studies. Because of the size of the studies (I think only a total of 350 patients on treatment in both studies), the FDA mandated that they do a monitoring study for safety purposes for 5 years with 500 patients (RENEW Study). THIS DID NOT DELAY THE USE OF NOVANTRONE. The study was being done concurrently to the general use of the drug. Ironically, lymphoma side effects developed in a few non-study patients, not RENEW patients (I think). The FDA just wanted formal pot-marketing surveillance. The RENEW study is very cheap (no MRI's, no EDSS blind evaluations, etc, they just pay investigators a little for a small quarterly or annual report. Lab work, DRUG, Echo's etc are covered by the patient or their insurance). They probably can follow these 500 patients for 5 years for the same price it would cost to follow 10-20 AFFIRM or SENTINEL patients with expensive evaluations, drug, MRI's, central labs, overhead, etc.

Will the FDA require a similar POST-MARKETING study? I think so. If so, BIIB/ELN will gladly accept this 'sentence' and set up a 1000 to 2000 multi site(about 80 to 100) post-marketing study..... not for efficacy (expensive) but just for safety (cheap). The expenses of this study will be less than the profit it generates with drug (as is like the case with the RENEW study). They can pay peanuts for a monthly 3 page checklist report. They can also use this as a 'marketing' study to target physicians of their choice. WIN-WIN-WIN, the FDA gets a formal process to keep the critics happy, the patients get their drug and BIIB/ELN get the drug out on the market with good PR. "
.

The efficacy level of any drug isn't worth much if the possibility of becoming very ill from it (like acquiring PML) becomes a reality.

Back in the early 60's, my uncle had MS. There was nothing available in North America to treat the disease. My aunt started searching around and made contacts with doctors in the then Soviet Union when she heard about a treatment they were experimenting with. It was called Nevoline (not sure of the spelling) and I have no idea at all how it worked. It was experiencing some great success.....until the patients started to become gravely ill!!!!

Until they come up with an answer as to why these two patients ended up with PML, Tysabri won't go anywhere! Hopefully they do find an answer quickly.

First some facts to put the tysabri/avonex versus PML in a little clearer light

1. Tysabri does not immune suppress patients beyond a slight amount - risk of infection was 2.1% for patients on tysabri versus 1.5% for patients on placebo

THUS TYSABRI IS NOT A POTENT IMMUNOSUPPRESSANT ON ITS OWN - AND THAT IS WHY PML HAS NOT BEEN SEEN IN TYSABRI MONOTHERAPY PATIENTS

2. That is not enough immunosuppression to allow PML to develop from unchecked JC virus replication

3.It seems that beta interferon treatment shifts the Th1/Th2 helper balance in favor of the Th2 (suppressive versus cytolytic T cells) helper cells - this is accompanied by an increased serum level of IL-10 - this is very similar to the shift in Th2 helper cells and IL-10 serum increases seen in HIV patients - but this is not enough to trigger PML as can be supported by the fact that PML has never been seen in avonex treated patients

THIS IS A COMPLETELY DIFFERENT IMMUNOSUPPRESSIVE MECHANISM AND ACTS ON THE T-CELLS THAT REACH THE BRAIN DESPITE TYSABRI TREATMENT - BUT NOW WHEREAS TYSABRI REDUCES THE AMOUNT OF T-CELLS THAT CAN GAIN ACCESS TO THE CNS TO ATTACK THE MYELIN ON NEURONS AND MAKE MS PLAQUES THE ADDITION OF BETA INTERFERON SHIFTS THE ENTIRE BALANCE OF T HELPER CELLS TOWARDS THE TH2 TYPE - THESE ARE SUPPRESSIVE AND FAVOR THE PRODUCTION OF ANTIBODIES VERSUS CYTOLYTIC T CELLS

This quote is from Weber F et al , annals of neurology 2001

"The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity." -

THIS IS PRECISELY THE SHIFT THAT AVONEX CAUSES - THE ACTION OF AVONEX IS TO IMPAIR TH1 HELPER CELLS AND FAVOR TH2 HELPER CELLS

***** THUS AVONEX TREATMENT IS A DRUG THAT IMPROVES THE CYTOKINE/HELPER CELL ENVIRONMENT BECOME MORE FAVORABLE FOR PML/JC VIRUS ACTIVATION

4. That is where tysabri comes in - it limits T cell passage through the blood brain barrier in the brain - thus it reduces the numbers of T cells present to cause MS plaques but also control JC virus - alone it also doesn't seem to put patients at risk for PML according to the monotherapy data

5. It seems that when you add the two together you shift the Th1 vs Th2 helper cell ratio in favor of the Th2 helpers (suppressive) (avonex) at the same time you limit the access of T cells (tysabri) - so the immunosupressive risk is additive

6. Then you add on the other immunosuppressive treatments that these patients may have had (MS patients that are progressing despite avonex are usually treated with steroids for each flare-up and novantrone or other chemo drugs and all of these are immunosuppressive) - so this is another additive risk for immunosuppression

THUS IT IS A CASE OF ADDITIVE IMMUNOSUPPRESSION - AND THUS TYSABRI MONOTHERAPY SHOULD BE PROVEN TO NOT BE A CAUSE OF THE PML AND THAT IS WHY IT HAS NOT BEEN SEEN IN ANY TYSABRI ALONE PATIENTS

PLUS YOU ALSO HAVE TO FACTOR IN THE PML RISK - even in patients with AIDS the PML rate is only 1-5% thus there is an additional risk factor that is probably patients specific

The risk of treating a patient with two drugs is far beyond the risk of each drug separately

If you have an 80 year old with high blood pressure - if you give him one drug that is safe he is OK, if you give him a second drug that is safe and he only take it then he is OK

If you give him both and they act synergistically and his blood pressure drops dangerously low - he can develop dangerous blood clots and the low blood pressure in the brain can cause necrosis of the hippocampus and simulate a stroke

If this happens would you expect that drug 1 and 2 would both be taken off the market to understand the intereaction? absolutely not!

With the between 40,000 and 100,000 deaths projected from adverse multiple drug interactions in the US this year - if you used this as your way way of deciding what drugs to pull - you would take the whole drug industry off the market.

The risk of a combination of drugs is not just the addition of one drug plus the other.
In time this will become obvious - but it should already be quite obvious "
.

The scientific info in your post re: the TH1 & 2 cells plus the other mechanisms involved, have been known for quite some time to researchers. I guess the question I have is why Biogen would combine Avonex and Tysabri at the same time while doing a major trial with Tysabri. It was going to take at least two years to really find out how Tysabri would do yet they combined it with another potent drug.

Makes me wonder if my previous answer to Arron about Biogen running the combo trial in the attempt to protect revenue may be more than just a guess!

I attended an MS retreat this weekend along with my husband. I questioned several people w/MS, on how they felt about Tysabri now.

The overwhelming reponse, acutally the only one I received was...
I would start back on it tomorrow if it were available or I'm eager for it to come back on the market, so I can start it. Obviously some people feel strongly that it will be back again.

I can certainly understand that feeling of those MS patients in wanting to go back on Tysabri. But until the researchers come up with a scientific answer as to what happened to those two patients and how to avoid a similar situation again, it won't be made available.

I can certainly understand that feeling of those MS patients in wanting to go back on Tysabri. But until the researchers come up with a scientific answer as to what happened to those two patients and how to avoid a similar situation again, it won't be made available.

Harry

Harry,
Of course common sense would tell us, that you are correct. I just thought it was interesting, that even in light of recent events, people are still very much behind Tysabri and willing to take a chance.
Cooly

HarryZ wrote:But until the researchers come up with a scientific answer as to what happened to those two patients and how to avoid a similar situation again, it won't be made available.

The PML problem was a problem with Ty in combo, so I am sure will wont see Ty back out in combo without an explanation. But as a monotherapy? I hear what you say about not finding unlooked for problems but I'm not so sure we wont see a monotherapy creeping out before the PML effect is explained. Now that may be cynicism tinged with optimism.

THREE MONTHS AGO, THE FEDERAL DRUG ADMINISTRATION APPROVED A NEW PROMISING DRUG FOR MULTIPLE SCLEROSIS PATIENTS. BUT, TWO WEEKS AGO THE MANUFACTURER OF TYSABRI PULLED IT FROM THE MARKET AFTER A PATIENT DIED AND ANOTHER BECAME CRITICALLY ILL.

IN THIS MORNING'S 13 HEALTHWATCH, NEWS 13 ANCHOR KELLY SCHULZ LOOKS AT WHAT'S NEXT FOR PATIENTS ON TYSABRI.

SCOTT DREW HAS BEEN ON TYSABRI FOR MORE THAN TWO YEARS.
MOST OF THAT TIME HE WAS PART OF A NATIONAL CLINICAL TRIAL HERE. NEWS THAT TYSABRI WAS BEING PULLED FROM THE MARKET SURPRISED HIM, "I was pretty shocked."

TYSABRI WAS PULLED WHEN ONE PATIENT DIED AND ANOTHER BECAME CRITICALLY ILL.

Dr. Patricia Fodor said, "There were two patients in clinical trials, both of whom were on avonex who developed a very rare brain infection called PML."

BOTH PATIENTS WERE ON TYSABRI ALONG WITH THE MS DRUG AVONEX.

OVER THE NEXT SEVERAL MONTHS, RESEARCHERS WILL BE LOOKING AT WHETHER THE COMBINATION OF TYSABRI WITH THE DRUG AVONEX IS CAUSING THE PROBLEM.

IN A PRECAUTIONARY MOVE, ALL THE PATIENTS ON TYSABRI WILL UNDERGO MRI TO MAKE SURE THE DRUG DIDN'T CAUSE ANY PROBLEMS FOR THEM.

IT'S HOPED IN THE NEXT THREE TO SIX MONTHS, TYSABRI MAY BE BACK ON THE MARKET, "I think they've proven the drug tysabri is good. I think they need to research more in certain situations bad combination. The drug does work. It gives MS patients another option to treat the disease. Hopefully they'll put it back on the market. I'd go back on it, if they do."

DR. FODOR'S PATIENTS ARE CURRENTLY OFF TYSABRI AND AVONEX FOR THE NEXT SEVERAL MONTHS, WHILE FURTHER STUDY IS DONE.

I know that some people feel that it was Avonex in combo with Tysabari but I keep on going back to what Biogen's VP of research said during a NMSS webcast....that he didn't think Avonex in combo was repsonsible because it had 650,000 patient years of no PML incidents. I don't know what to think and the researchers don't know either.

I do believe that it is going to take longer than 3 to 6 months to figure this out but who knows...when a lot of money is at issue, some things have a tendency to happen more quickly!!

Biogen Idec Inc. may have pushed a combination multiple sclerosis treatment using its top drugs - Tysabri and Avonex - to fatten company profits without evidence the two meds were better than Tysabri alone, a leading MS researcher has charged.

The Cambridge biotech giant never tested Tysabri alone against Tysabri and Avonex, relying instead on tests of Tysabri vs. a placebo and Tysabri plus Avonex vs. just Avonex.

``What they should have done was a third arm of that study'' - comparing Tysabri vs. Tysabri with Avonex, Dr. Patricia Coyle, a neurology professor at the State University of New York at Stony Brook, told the Herald.

``Why didn't they do that?'' said Coyle, who also heads the school's MS center. ``From a marketing point of view, that wouldn't have been a good study. You want to sell all your drugs.''

Biogen and its partner, Elan Corp., pulled Tysabri last month after a patient on the combination treatment died of a rare neural disorder and another contracted it.

A Biogen spokeswoman defended the company yesterday.

``The (Tysabri vs. Tysabri plus Avonex) trial was designed for patients on existing therapies who experienced relapses,'' Amy Brockelman said. ``If we were concerned with cannibalizing Avonex, we never would have developed Tysabri.''

Tysabri won fast-track approval from the U.S. Food and Drug Administration in November based on tests showing it cut the rate of MS relapses by 66 percent, compared with Avonex's 30 percent to 40 percent rate. A second Biogen study showed patients on Tysabri and Avonex had 54 percent fewer relapses than those on Avonex alone.

``When you look at those two studies, you would as a doctor use the monotherapy (Tysabri alone), not the combination,'' Coyle said. ``We're talking a lot of money.''

Tysabri costs as much as $30,000 a year, including infusion fees, and Avonex runs about $15,000 a year.

Avonex was Biogen's top seller last year, with $1.42 billion in sales; but some experts estimated Tysabri would have doubled that.

Two other doctors agreed with Coyle's assessment of Tysabri.

``You can't really say that Tysabri plus Avonex was more effective than Tysabri alone,'' said Dr. Ugo Goetzl, who runs the Millennium Clinic in Durham, N.C.

Added Dr. Barry Singer, an MS expert at the Washington University School of Medicine in St. Louis: ``The hard science would have been to do the three-arm trial. Before the recall, I was planning on using Tysabri. There was a lack of evidence that the combination was more effective.''

One analyst thinks Biogen never did the third study ``for commericial reasons.''

``They wanted to protect their franchise (in Avonex),'' said Eric Schmidt, of SG Cowen Securities. ``The easiest way to put a stake in that franchise is to show Tysabri is more effective than Avonex

Who is online

This site does not offer, or claim to offer, medical, legal, or professional advice.
All treatment decisions should always be made with the full knowledge of your physicians.
This is MS does not create, endorse, or republish any content.
All postings are the responsibility of the poster. All logos and trademarks in this site are property of their respective owners. All users must respect our rules for intellectual property rights.